Effects of stress on endophenotypes of suicide across species: A role for ketamine in risk mitigation

Suicide is a leading cause of death and morbidity worldwide, yet few interventions are available to mitigate its risk. Barriers to effective treatments involve a limited understanding of factors that predict the onset of suicidal thoughts and behaviors. In the context of suicide risk, stress is a precipitating factor that is largely overlooked in the literature. Indeed, the pathophysiology of stress and suicide are heavily interconnected, underscoring the need to target the stress system in suicide prevention. In this review, we integrate findings from the preclinical and clinical literature that links stress and suicide. We focus specifically on the effects of stress on underlying biological functions and processes associated with suicide, allowing for the review of research using animal models. Owing to the rapid anti-suicidal effects of (R,S)-ketamine, we discuss its ability to modulate various stress-related endophenotypes of suicide, as well as its potential role in preventing suicide in those with a history of chronic life stress (e.g., early life adversity). We highlight future research directions that could advance our understanding of stress-related effects on suicide risk, advocating a dimensional, endophenotype approach to suicide research.